Life Sciences: Year In Review 2007

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Researchers studied the origin of cat domestication, variations in dog size, hormone structure in plants, and chemical changes in the proteins that package DNA. Genetic engineering created novel strains of rice and mosquitoes to combat malaria, and rice strains with human genes began to be grown commercially.

Zoological research in 2007 provided new insights into the domestication of cats. Cats were known to have been associated with humans as early as 9,500 years ago from archaeological evidence on Cyprus, but their evolutionary line from wild ancestors and the region where they were first domesticated had been uncertain. To determine the origin of cat domestication, Carlos A. Driscoll of the Laboratory of Genomic Diversity, Frederick, Md., and colleagues obtained and analyzed DNA from 851 individual nondomestic (wild) and domestic cats to determine their genotypes. The nondomestic cats included European cats, Near Eastern wildcats, central Asian cats, southern African wildcats, and Chinese desert cats, all of which were considered subspecies of Felis silvestris. The sample of domestic cats included both feral domestic cats and recognized breeds of housecats. A separate wild species, the sand cat (F. margarita) of North Africa and the Middle East, was chosen as the closest outgroup (group belonging to a separate evolutionary branch). Genetic mixing is extensive between feral domestic cats and wildcats throughout their geographic ranges, but the genetic evidence supported the conclusion that cats were first domesticated in the Middle East, presumably during the rise of agriculture in the Fertile Crescent. The investigators estimated that the common ancestor for the Near Eastern wildcat subspecies (F. s. lybica) and domestic cats lived approximately 131,000 years ago.

Nathan B. Sutter and Elaine A. Ostrander of the National Human Genome Research Institute, Bethesda, Md., and colleagues determined that a single allele (gene variant) is the major genetic determinant of body size in domestic dogs. The gray wolf (Canis lupus) is the accepted ancestor of the domestic dog (C. familiaris), but as a consequence of centuries of selective breeding, the latter had one of the greatest ranges of body size among terrestrial vertebrates. The largest dogs weighed 50 times more than the smallest. Several genetic explanations for the observed variability had been suggested, but none had been confirmed. The investigators located genetic sequences related to size on a section of chromosome 15 in the Portuguese water dog, a recognized domestic breed with a wide range in size. They discovered that an allele of the gene that encodes the insulin-like growth factor 1 (IGF-1) was present in small dogs but typically absent in large ones. The genetic association between body size and the IGF-1gene was also apparent in 14 small breeds of dogs and typically absent in 9 that were classified as giant breeds. IGF-1 had been shown in earlier studies to affect the body size of mice and humans. The findings helped clarify the genetic origin of size diversity among domestic dogs and also revealed how natural selection on a single gene could lead to rapid evolution in body size in species undergoing adaptive radiations.

Gibson, a Great Dane measuring 107 cm (42.2 in) tall at the shoulder, is seen striding alongside a …

Andrew F. Russell of the University of Sheffield, Eng., and colleagues provided insight into previously unrecognized benefits of cooperative bird-breeding systems in which nonbreeding helper males assisted in providing food for offspring. In such species the young are given more food when helper males assist with feeding, and helper males are presumed to benefit from kin selection (by being closely related to the offspring) or group augmentation (such as a greater efficiency in acquiring resources by being associated with other individuals). How females or offspring benefit from the presence of helper males, however, had been difficult to assess because when offspring received additional food, their fledgling size and survival were often unaffected. The investigators compared breeding units of the superb fairy-wren (Malurus cyaneus) of Australia. Some of the breeding units consisted only of breeding pairs, and others contained helpers. In cooperative breeding units with helpers, the young received 19% more food than in breeding units without helpers. When helpers were present, however, mother wrens laid smaller eggs that had reduced nutritional content and produced smaller chicks. The benefits that offspring received when helpers were present were thereby concealed by the overall reduction of the females’ investment in their eggs. Experiments in which eggs laid by a female in a group with helpers were substituted for eggs laid by a female in a breeding pair and vice versa gave further confirmation that the birds compensated for the presence or absence of helpers by adjusting egg and hatchling size. For example, chicks from helper-group eggs incubated and raised only by breeding pairs exhibited reduced growth and survival. (The incubation period and the time that the superb fairy-wren chicks remained in the nest did not vary.) The investigators showed that the advantage for females when helpers were present was the reduction in their reproductive investment, which increased their fitness and probability of breeding again.

Two independent teams of researchers reported on two major genome-sequencing studies. The Rhesus Macaque Genome Sequencing and Analysis Consortium, under the leadership of Richard A. Gibbs of Baylor College of Medicine, Houston, sequenced the genome of the rhesus macaque monkey (Macaca mulatta). The species had been used as the premier nonhuman primate in biomedical research for decades, including studies on viruses that caused flu, polio, and AIDS, and it was the species in which the blood protein known as the Rh factor was first identified. Using a genetic map with an estimated 20,000 genes, researchers expected to be able to target particular traits expressed in individuals and use genetic pathways to identify and manipulate specific genes that were responsible for the trait. In addition to the value of the genome sequence for biomedical research, the sequence provided unprecedented opportunities for examining at the genome level the evolutionary relationships and changes between humans, chimpanzees (the closest living relative of humans), and rhesus macaques, which had a common ancestor 25 million years ago. A team led by Tarjei S. Mikkelsen of the Massachusetts Institute of Technology sequenced the genome of the South American gray short-tailed opossum (Monodelphis domestica) in the first such work on a marsupial. The species had been used frequently in genetic research and in the fields of immunology and neurobiology. Comparison of the genome of a metatherian (marsupial) with those genomes available for eutherian (placental) mammals offered the prospect of insight into genomic function, organization, and evolution among mammal lineages. An initial finding was that in the opossum only about 1% of the genetic regions that code for amino-acid proteins, compared with about 20% for noncoding regions, had evolved since the divergence of metatherians and eutherians 180 million years ago.

Life in the deep-ocean portions of the Southern Ocean, which encircles Antarctica, had been poorly explored compared with other oceans and with the shallow-water habitats of the Antarctic region. Angelika Brandt of the Zoological Museum, Hamburg, and colleagues provided the first overview of the zoological diversity of these deep-sea communities, based on their investigations in the Weddell Sea. A variety of sampling techniques, including underwater photography, bottom coring, and bottom and midwater trawling, were used during three expeditions between 2002 and 2005, at depths as great as 6,348 m (20,827 ft). The zoological distinctiveness and unexplored nature of the deep waters of the Southern Ocean were apparent in several ways. The collection of samples of more than 13,000 crustaceans known as isopods yielded 674 species, of which 86% had previously been unknown, and the number of isopod species found was 1.8 times greater than that known from the shallower depths of the entire Antarctic continental shelf. Numerous species were found among other major taxonomic groups, including foraminifers (158), nematodes (57), ostracods (more than 100), polychaete worms (more than 200), shelled gastropods and bivalves (160), and sponges (76). At least 20% and for most of the groups more than 50% of the species collected were new to science. The investigators noted several biogeographic trends. For example, among their deep-sea samples of isopods, ostracods, and nematodes—organisms that typically disperse poorly—there were species characteristically associated with the continental shelf and many not known outside the Southern Ocean. Organisms that were more likely to disperse, such as foraminifers, and that were found at great depths were more closely related to fauna found in other oceans, in particular the Atlantic Ocean. The observations dismissed an earlier perception that species diversity in the deep areas of the Southern Ocean is low, and they offered new opportunities for exploring the zoogeographic patterns and evolutionary relationships among the deep-sea and continental fauna.

Shannon L. LaDeau and Peter P. Marra of the Smithsonian Migratory Bird Center, Washington, D.C., and A. Marm Kilpatrick of the Consortium for Conservation Medicine, New York City, used long-term records from the North American Breeding Bird Survey program to assess the impact of the West Nile virus on 20 species of birds. Adjustments were made for anticipated changes in population levels caused by climatic and ecological factors. Noticeable declines that coincided with the arrival of the virus in 1999 in New York were found in seven species. The greatest impact was observed in the population of American crows, which declined by as much as 45%. All of the bird species, including American robins and blue jays, were commonly associated with urban and suburban areas. The findings had implications concerning links between birds and humans, who were also susceptible to West Nile virus and other bird-transmitted pathogens.

Botany

In 2007 genetically modified (GM) plants that incorporated human genes began to be grown commercially for the first time. The plants, strains of rice modified to express human protein in their seeds, were made by Ventria Bioscience, a biotech company headquartered in Sacramento, Calif. Commercial planting of the rice in designated fields in Kansas was approved in May 2007 by the U.S. Department of Agriculture. The human proteins produced by the GM rice strains were lysozyme, lactoferrin, and serum albumin, which are commonly found in human breast milk. The company claimed that the rice-manufactured proteins could be taken orally to combat diarrhea and anemia, a potentially important application for less-developed countries. Before products made from the rice could be sold to consumers, however, further regulatory approvals would be needed. Critics of the project feared that the strains could contaminate normal rice strains and people would then unwittingly be exposed to the GM proteins by eating them in food. The journal Nature Biotechnology compared growing such pharmaceuticals in crops to packaging pills in candy wrappers. The USDA believed that the rice would not escape into the environment or enter the food supply, thanks to such safeguards as planting the GM rice more than 480 km (300 mi) away from any other rice farms.

GM rice also showed promise for producing human vaccines. Japanese scientists engineered a strain of rice that carried a vaccine for cholera, which is caused by Vibrio cholerae bacteria. When the rice was fed to mice in scientific trials, it produced antibodies that targeted the vulnerable mucosal sites where cholera infection first occurs. In contrast, conventional vaccines that are administered via injection are less targeted. The rice-based vaccine also had the advantage that it could be stored at room temperature; conventional vaccines required refrigeration. Similar types of GM plants developed for vaccines could be particularly useful against other viruses that attack mucosal tissues in the body, such as human immunodeficiency virus (HIV).

Zhixiang Chen of Purdue University, West Lafayette, Ind., and colleagues genetically modified plants to resist infection from the Cauliflower mosaic virus (CaMV), a virus that attacks many agriculturally important plants, including cauliflower, broccoli, and cabbages. CaMV uses reverse transcription to create copies of itself and spread the infection. In reverse transcription, the virus’s RNA is copied into DNA after it latches onto a victim cell. In their investigation the researchers infected the plant Arabidopsis thaliana with cauliflower mosaic virus and found that reproduction of the virus makes use of cyclin-dependent kinase C complex (CDKC), a protein complex found in the plant cells. By blocking CDKC the scientists were able to make the plant completely resistant to infection from CaMV. This research might lead to ways of combating HIV, because HIV also uses reverse transcription and the same protein complex (referred to in human cells as positive transcription elongation factor b) to multiply and spread the infection.

For the first time, scientists determined the structure of a plant hormone receptor and the means by which the receptor interacts with a hormone. A team led by Ning Zheng of the University of Washington School of Medicine studied the hormone receptor, TIR1, a type of enzyme known as a ubiquitin ligase, and its interaction with indole-3-acetic acid and two other plant hormones that are collectively known as auxin. Auxin plays an essential role in the growth and development of plants, and there was much conjecture about the nature of the receptor-hormone binding. The scientists extracted TIR1 from the plant Arabidopsis and purified it into crystals. Using X-ray images of the crystals, they determined the enzyme’s three-dimensional structure. The crystals were then soaked in auxin and X-rayed again, which revealed that auxin functions as a “molecular glue” that improves the ability of TIR1 to bind its peptide target. In the absence of auxin, TIR1 does not bind its target as tightly. This discovery not only was a major advance for plant biology with important potential implications for agriculture but also might lead to new treatments of human cancers, because TIR1 is similar to human ubiquitin ligases that are involved in cancer. The scientists expected that these human enzymes might be affected by small molecules like auxin and that chemists might be able to synthesize such molecules as a new type of cancer drug.

The parasitic plant Rafflesia arnoldii has the world’s largest single flower, a red-and-white bloom that measures up to 1 m (3.3 ft) in diameter and stinks of rotting flesh to attract the small flies it needs for pollination. The classification of this and the other 20 or so species of rafflesias had long baffled scientists. A team led by Charles Davis at Harvard University examined eight genes of R. arnoldii and determined that the plant belongs to the Euphorbiaceae family, which includes poinsettias and bells of Ireland as well as commercially important crops such the rubber tree, castor-oil plant, and cassava. Given the inferred phylogeny, the scientists estimated that flower diameter among the plants in the evolutionary lineage of R. arnoldii underwent about a 73-fold increase over about 46 million years, one of the most dramatic cases of evolutionary size increase reported for any plant or animal.

The giant single flower of the parasitic plant Rafflesia arnoldii is inspected by …

Frans Lanting/Corbis

Biologist Santiago Ramírez and his colleagues at Harvard University identified the first fossilized remains of an orchid. The finding allowed them to work out the origins of orchids and solve a long-standing dispute over their evolution. Although orchids formed the largest family of flowering plants, they rarely fossilized. The fossilized remains that were found were particles of orchid pollen that covered a bee found preserved in fossil amber that was 15 million–20 million years old. The pollen was identified as belonging to an orchid from the orchid subtribe Goodyerinae. The scientists compared the fossil pollen with pollen of modern-day plants and reconstructed an evolutionary tree for orchids. On the basis of the assumption that the plants underwent a relatively constant rate of evolution, the oldest common ancestor of the orchid family dated from 76 million to 84 million years ago, in the Late Cretaceous Period. “The dinosaurs could have walked among orchids,” said Ramírez.

Molecular Biology and Genetics

Epigenetics Takes Centre Stage

The genome is often called the blueprint of life, but it is the epigenome—the way the genome is modified chemically and packaged—that defines how the information in the blueprint is read and applied. Genetic information is encoded in the sequences of nucleotides that make up the DNA that is passed from parents to offspring. In contrast, epigenetic information, though heritable by cells or organisms, is not specific to the nucleotide sequence of the transmitted nucleic-acid genome. The field of epigenetics, the study of the epigenome and its functional significance, has recently exploded, revolutionizing the fields of genetics and developmental biology. For example, in 2007 researchers led by Keji Zhao of the National Institutes of Health, Bethesda, Md., and by Eric Lander and Bradley Bernstein of the Broad Institute, Cambridge, Mass., reported how they were able to identify and map key genomewide epigenetic modifications in mammalian cells.

Epigenetics is known to involve a number of possible chemical modifications to DNA and to the proteins called histones that package the DNA into a complex substance, called chromatin, inside a cell. One principal type of modification is DNA or histone methylation. Methylation can be transient and change rapidly during the life span of a cell or organism, or it can be largely permanent once set early in the development of the embryo. (Other largely permanent chemical modifications also play a role; these include histone acetylation, ubiquitination, and phosphorylation.) The specific location of methylation on a histone protein can be important. For example, Zhao and colleagues identified specific histone modifications that distinguish actively expressed regions of the genome from repressed regions and found histone modifications that correlate with chromosome banding patterns. Lander and Bernstein similarly determined specific histone modifications that distinguish actively expressed genes, genes poised for expression, and repressed genes in different kinds of cells.

Epigenetic changes not only influence the expression of genes in plants and animals but also enable the differentiation of distinct cell types from pluripotent stem cells early in development. In other words, such changes allow cells to become specialized as liver cells, brain cells, or skin cells, for example, even though the cells all share the same DNA and are ultimately derived from one fertilized egg. As the mechanisms of epigenetics have become better understood, researchers have recognized that the epigenome also influences a wide range of biomedical conditions. This new perception has opened the door to an understanding of normal and abnormal biological processes and promises interventions that might prevent or ameliorate certain diseases.

Epigenetic contributions to disease fall into two classes. One class involves genes that are themselves regulated epigenetically, such as the imprinted (parent-specific) genes associated with Angelman syndrome or Prader-Willi syndrome. Clinical outcomes in cases of these syndromes depend on the degree to which an inherited normal or mutated gene is or is not expressed. The other class involves genes whose products participate in the epigenetic machinery and thereby regulate the expression of other genes. For example, the gene MECP2 encodes a protein that binds to specific methylated regions of DNA and contributes to the silencing of those sequences. Mutations that impair the MECP2 gene can lead to Rett syndrome.

Many tumours and cancers are believed to involve epigenetic changes attributable to environmental factors. These changes include a general decrease in methylation, which is thought to contribute to the increased expression of growth-promoting genes, punctuated by gene-specific increases in methylation that are thought to silence tumour-suppressor genes. Epigenetic signaling attributed to environmental factors has also been associated with some characteristics of aging by research that studied the apparently unequal aging rates in genetically identical twins.

One of the most promising areas of recent epigenetic investigation involves stem cells. It has been understood for some time that epigenetic mechanisms play a key role in defining the “potentiality” of stem cells. Only recently, however, as those mechanisms have become clearer, has it become possible to intervene and effectively alter the developmental state and even the tissue type of given cells. The implications of this work for future clinical intervention for conditions ranging from trauma to neurodegenerative disease are profound.

A New Weapon in the War on Malaria

Malaria is an infectious disease that affects more than 350 million persons each year, killing more than a million. It results from infection by any of four species of the protozoan parasite Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae. The parasite has a complex life cycle that proceeds through distinct phases in an infected human host and an infected Anophelesmosquito. The mosquito acquires Plasmodium protozoa when it sucks blood from an infected person. The mosquito harbours the parasites as they proceed through stages of reproduction and maturation. The mosquito subsequently transmits them back to humans when it bites and injects saliva contaminated with Plasmodium.

The struggle to reduce or eliminate malaria worldwide has been long, costly, and at times controversial. The measures have included the reduction of local mosquito populations, reduction of mosquito access to humans (by using insecticide-treated bed nets, for example), and medications, such as quinine or primaquine, that combat the infection in a human host. Efforts to devise a safe and effective vaccine continue but have yet to bear fruit. In recent years, however, a new weapon has emerged that might prove the best solution of all—a genetically modified Anopheles mosquito that is itself resistant to infection by Plasmodium.

Since the mid-1990s, several groups have produced transgenic mosquitoes that are resistant to Plasmodium infection. One group, for example, modified mosquitoes to express a small amount of a substance called SM1 dodecapeptide in cells that line the salivary gland and gut of the mosquito. This peptide binds to the same cell-surface receptors used by Plasmodium to recognize and invade mosquito cells. Overexpression of this peptide in target tissues therefore competitively inhibits entry of the Plasmodium parasite. A key question was whether transgenic mosquitoes could thrive in the wild among natural mosquito populations, since the genetic manipulations that were required for establishing Plasmodium resistance could render the resulting mosquitoes less “fit” than their wild-type (normal) peers. In 2004 a team of researchers directed by Marcelo Jacobs-Lorena from Johns Hopkins University, Baltimore, Md., reported a major breakthrough. The team had identified a line of transgenic mosquito that expressed the SM1 peptide (and consequently was resistant to Plasmodium infection) yet remained as fit as its wild-type peers when fed on the blood of mice that had not been infected by Plasmodium. Equal fitness, however, was no guarantee of success in the field, especially given the much greater number of wild-type mosquitoes.

The mature eyes (bottom) and larvae (top) of Anopheles mosquitoes. The specimens …

Johns Hopkins Malaria Research Institute/Marcelo Jacobs-Lorena

In the spring of 2007, Jacobs-Lorena and colleagues reported the striking observation that their transgenic mosquitoes demonstrated a clear fitness advantage—relative to wild-type mosquitoes—when fed on the blood of mice that were infected by Plasmodium. To test the relative fitness of their transgenic mosquitoes in the context of Plasmodium infection, the researchers conducted a series of experiments in which initial populations that were made up of equal numbers of wild-type and transgenic mosquitoes were allowed to interbreed and expand for 13 generations. One hundred individual mosquitoes from each new generation were tested to ascertain the relative proportion of wild-type and transgenic subpopulations. The results clearly demonstrated a slow but steady increase in the proportion of transgenic mosquitoes, with a plateau of about 70% transgenic mosquitoes reached in each population by the ninth generation.

These results were exciting for three reasons. First, if resistance to Plasmodium infection provided a fitness advantage to mosquitoes, then even a small number of transgenic mosquitoes released into a Plasmodium-infested area would increase until such mosquitoes provided an effective deterrent to human transmission. Second, if the vast majority of mosquitoes in currently Plasmodium-infested areas could be rendered disease-free, malaria might be controlled or eliminated without the need for widespread use of chemicals, deforestation, draining of wetlands, or other environmentally destructive measures. Finally, this strategy might be directed at other mosquito-borne infectious diseases, such as yellow fever, dengue, and West Nile virus encephalitis.